This application is a continuation of International Application PCT/JP01/02028, filed on Mar. 14, 2001, and claims priority to Japanese Patent Application No. 2000-076887, filed on Mar. 17, 2000, both of which are incorporated herein by reference in their entireties.
1. Field of the Invention
The present invention relates to novel stilbene derivative crystals. More specifically, the invention relates to a novel crystal form of (Z)-N-[2-methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]phenyl]-L-serinamide hydrochloride, which is useful as an effective ingredient of a carcinostatic agent (anticancer agent), methods for producing the same, and the use thereof.
2. Discussion of the Background
Stilbene derivatives of a specific structure exhibit anticancer activity (action), and are useful compounds as effective ingredients of carcinostatic agents (see Japanese Patent Kokai Publication JP-A-8-301831, International Publication WO 99/51246, both of which are incorporated herein by reference in their entireties, and the like).
(Z)-N-[2-methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]phenyl]-L-serinamide hydrochloride represented by the following structure (structural) formula (1): 
is particularly excellent as an effective component (ingredient) for the development of a pharmaceutical agent among a great number of stilbene derivatives with a carcinostatic activity. However, the inventors have found that the crystals of this compound as recovered by a general method (hereinafter, the crystal type or form recovered by the general method is referred to as xe2x80x9cType Ixe2x80x9d, and the crystals of this type is referred to as xe2x80x9cType I crystalsxe2x80x9d) adsorbs water (water vapor) to a degree roughly (approximately) proportional to the water vapor pressure (relative humidity), i.e., the Type I crystals adsorb water depending on the surrounding humidity. The inventors have also found that the quantity of the adsorbed water by the Type I crystals is fairly large.
Such crystals which are unstable in the presence of water are not preferable for drug preparation. For the production of drugs and dosage forms (pharmaceutical preparations) thereof, a stable crystal which exhibits reduced (very little) water adsorption and less (very little) water (water vapor) adsorption up to around a relative humidity of 80% is preferable.
Accordingly, it is one object of the present invention to provide crystals of the stilbene derivative represented by the structural formula (1), which exhibit an extremely low water (water vapor) adsorption level as described above, namely a crystal form which is stable to water (moisture).
It is another object of the present invention to provide novel method for producing such a crystal.
It is another object of the present invention to provide novel pharmaceutical compositions which comprise such a crystal.
It is another object of the present invention to provide novel method for producing such a pharmaceutical composition.
It is another object of the present invention to provide novel methods of treating cancer by administering such a pharmaceutical composition to a subject in need thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" investigations of crystals of (Z)-N-[2-methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]phenyl]-L-serinamide hydrochloride as represented by the structural formula (1) described above, and their discovery of a novel crystal thereof which is stable to water (moisture) (hereinafter, the crystal form is referred to as xe2x80x9cType IV crystalxe2x80x9d), which differs from the crystal type (Type I) obtained by the general method. As specifically shown in the X ray powder diffraction pattern described below, the Type IV crystal obtained in accordance with the present invention is a novel crystal which is different from the crystal type obtained by the general method. The present inventors have found that the novel crystal is so stable to water (moisture) that the crystal adsorbs extremely little water (water vapor) up to around a relative humidity of 80%. The inventors have also found that a trace content of water in a solvent used for the crystal formation (crystallization) thereof is a factor determining such crystal type. Based on these various findings, the present invention has been achieved.
Thus, in a first embodiment, the present invention provides the novel crystal, more specifically, a Type IV crystal of (Z)-N-[2-methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]phenyl]-L-serinamide hydrochloride represented by the structural formula (1), which is a novel crystal (Type IV crystal) differing from that of the crystal recovered (obtained) by the general method, as shown in the X ray powder diffraction pattern, and which has peaks at least at 13.4xc2x0, 18.7xc2x0, 19.4xc2x0 and 22.5xc2x0 (2xcex8) in the X ray powder diffraction pattern.
In other embodiments, furthermore, the present invention provides the use thereof (application, etc.) and a method for producing the crystal.
More specifically, the present invention encompasses the following embodiments.
(1) The crystal of the present invention described above, having a X ray powder diffraction pattern which contain peaks at least at 11.1xc2x0, 13.4xc2x0, 14.2xc2x0, 18.7xc2x0, 19.4xc2x0, 22.5xc2x0 and 23.4xc2x0 (2xcex8).
(2) The crystal of the present invention described above and the crystal described above in (1), which adsorbs water (water vapor) at a level of less than 20 ml/g (preferably, less than 15 ml/g or so) at a relative humidity of 80%, on a prepared water (water vapor) adsorption isotherm (isothermal line) (see Mitsuiki et al., J. Agric. Food Chem., vol. 46, No. 9, pages 3528-3534 (1998)).
Here, the water (water vapor) adsorption level represents the water vapor volume occupying one gram crystal (ml/g) at 0xc2x0 C. and one atmospheric pressure.
Further, preferably, the water (water vapor) adsorption levels at relative humidity of 40, 60 and 80% are less than about 8 ml/g (more preferably, less than about 6 ml/g), less than about 16 ml/g (more preferably, less than about 9 ml/g) and less than about 20 ml/g (more preferably, less than about 15 ml/g), respectively.
Water (water vapor) adsorption isotherms both in adsorption and desorption processes (water vapor adsorption levels measured by the method for measuring water (moisture content) when humidity increases and decreases to dryness) are shown in FIGS. 3 and 4. Preferably, a smaller level of the resulting two levels satisfies the above numerical range.
(3) The crystal of the present invention and the crystals described above in (1) and (2), which can be crystallized using a solvent, which may be a mixed solvent, containing water at 2% by weight at the maximum, preferably a mixed solvent of methanol-isopropyl acetate which contains substantially no water.
(4) A carcinostatic agent (anticancer agent) such as an oral dosage form or a parenteral dosage form (injections, etc.) containing the Type IV crystal described above or being produced by using the Type IV crystal described above (which may contain carrier(s) used in the method for producing a dosage form (a pharmaceutical preparation).
In other words, the present invention encompasses the use of the Type IV crystal as a carcinostatic agent, and a method of use of the Type IV crystal for a carcinostatic effect such as therapeutic treatment, amelioration (improvement), progress prevention, prophylaxis (prevention), etc. of cancer, comprising administration of the crystal to an animal such as a human in need of the carcinostatic effect.
Incidentally, depending on the symptom and the like of the patient or the like, the appropriate dose of the crystal in this case can be easily determined, based on the method for use of routine carcinostatic agents and known methods for use of the carcinostatic agents. The appropriate carrier for use in the production of dosage forms thereof can also be easily determined on the basis of routine pharmacological methods.
(5) A method for producing a crystal of (Z)-N-[2-methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]phenyl]-L-serinamide hydrochloride represented by the structural formula (1) described above containing a crystallization step therefor, in which the crystallization step uses a crystallization solvent containing water in a maximum amount of 2% by weight (an amount of 2% by weight or less) for the crystallization of the Type IV crystal thereof.
The water content of the crystallization solvent, is more preferably a maximum of approximately 1% by weight (approximately 1% by weight or less), and still more preferably at the most approximately 0.5% by weight (approximately 0.5% by weight or less). Most preferably a solvent which contains substantially no water can be used. In the case when a mixture solvent (a mixed solvent) of more than one solvent is used as the crystallization solvent, the entire crystallization solvent (i.e., all of the solvents together) preferably contains such a small amount of water content in total as described above. Accordingly, in the case when a combination of a good solvent(s) and a poor solvent(s) is used for re-precipitation, for example, the whole mixture system of the good solvent(s) and the poor solvent(s) to be used may be adjusted to the low water content described above. Here, a combination of the good solvent(s) and the poor solvent(s) to be used for re-precipitation is also encompassed within the range of the term xe2x80x9cmixture solventxe2x80x9d described above, according to the method of the present invention described above.
(6) The method for producing the crystal (Type IV crystal) described above, where the solvent to be used in the crystallization step is a combination (mixture solvent; mixed solvent) of a good solvent(s) and a poor solvent(s) for the compound (1).
(7) The method for producing the crystal (Type IV crystal) described above, where the good solvent(s) includes at least one compound selected from alcohols, chloroform, acetone, and acetonitrile, and the poor solvent(s) includes at least one compound selected from acetate esters (acetic acid esters), ethers, saturated hydrocarbons, and cyclic saturated hydrocarbons.
(8) The method for producing the crystal (Type IV crystal) described above, where the crystallization step is via (through) re-precipitation method.